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Final Report Summary - ODICODAS (Optical dissection of cortical dopamine signaling)

Executing a movement, deciding whether to perform a specific action or learning motor skills are things of our every day life. The part of our brain that is mainly in charge of such processes is the motor cortex. In order to fulfill its role, the motor cortex integrates information originating in other brain regions and computes a final motor output that is sent to brainstem and spinal cord motor centers. In this way, the motor cortex controls the execution of movements.
The motor cortex receives a wide variaty of inputs stemming from other cortical areas (such as the sensory cortex), neuromodulatory nuclei (such as noradrenergic or cholinergic inputs) and, importantly, motor related information from the basal ganglia and cerebellum both of which enter the cortex via the motor thalamus.
The thalamus makes contact with the motor cortex through the thalamo-cortical axons. Recent anatomical work has demonstrated that thalamo-cortical axons conveying basal ganglia information contact the most superficial layer 1 of the cortex while those conveying cerebellar information do it onto the intermediate layer 2/3. Furthermore, basal ganglia and cerebellum are involved in different aspects of behavior. While the basal ganglia would be related to the learning, planning and selection of appropriate motor plans, the cerebellum would be more related to the real time correction and learning of motor skills. Thus, it is tempting to ask what specific role each one of these pathways play at the level of the motor cortex.
Despite our current understanding of the cortex in motor control, several issues remain open regarding the motor-related information arriving from the thalamus to the motor cortex:
1. What is the exact timing of thalamo-cortical activity in the frontal cortex during motor preparation, execution and learning?
2. Is the thalamo-cortical activity a widespread signal affecting simultaneously different cortical areas, or different kinds of information are sent to small specialized cortical areas?
3. Are the thalamo-cortical inputs to the motor cortex necessary for the actual motor execution or do they play another role in the motor control?

By combining state of the art behavioral techniques, cutting edge two-photon microscopy and genetically engineered tools we investigated the nature of the thalamo-cortical information arriving to layer 1 of the motor cortex in rodents.
We firstly developed a novel behavioral task in which mice are trained to associate a vibrotactile stimulation with a reaching movement of their forepaw. The stimulation can be a high frequency or low frequency vibration. At the end of each vibration, there is a “delay” period during which the mice have to wait for a “go” signal, upon which they perform a reaching movement towards one of two possible targets (left or right). If the mice reach for the correct target they gain a reward, otherwise there is a “time-out” of ten seconds. After 3-4 weeks of training, mice learn the correct association and perform at 76±4.8% correct choices. “Left” or “right” trials types are presented randomly to ensure that the mice learnt the correct association.
Next, we used a two photon microscope to study the activity of thalamo-cortical axons of the mice while they were performing the behavioral task. Thalamo-cortical axons were targeted to express a fluorescent protein (GCaMP6) whose intensity increases with the level of the neuronal activity. As expected, we found that thalamo-cortical axons projected to different areas of the frontal cortex, including the motor and somatosensory cortices. Also, we found that the thalamo-cortical activity was highest during behaviorally active periods, while it was minimal during quiet periods (resting time between trials) and under anesthesia. These results suggest that thalamo-cortical activity is highly engaged in the behavioral task.
We performed a deep analysis of individual axons to determine whether thalamo-cortical activity was related to specific aspects of the behavioral task in different regions of the cortex. Thalamo-cortical axons displayed a wide variety of task-related activity, including the vibration, delay and motor execution periods. The most prominent activity was related to the movements and it was widespread across different cortical areas. On the other hand, vibration related activity was present in the vicinity of the somatosensory cortex and delay related activity was mainly present in the more anterior region of the motor cortex. These results indicate that thalamocortical activity is a widespread signal with cortical-region specializations that is not just related to the motor execution itself, but also to the periods before movement onset, suggesting a possible movement preparatory role (delay activity) and sensory role (vibration activity).
While many thalamo-cortical axons were active during both trial types (“left” and “right”), subsets of thalmocortical axons displayed preference for one of both trial types. Moreover, we found some individual axons active during the delay period whose activity predicted the actual reaching movement performed by the mouse (left or right) irrespective of whether the movement was correct or not. These results suggest that thalamocortical axons might convey information related to the motor plan selection (reach to the left or reach to the right).
In summary, we have shown that the thalamo-cortical pathway conveys specific task related information to the motor cortex that might be key for the correct performance of the task (sensory discrimination, movement preparatory activity and movement related activity). However, to ellucidate whether this information is necessary for the behavioral output or it plays a different role in the behavioral task, we are performing additional experiments by which we will transiently inactivate thalamo-cortical axons at different moments of the behavioral task and we will analyze the effect of such inactivation on the performance.

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